The ovarian/menstrual cycle is a complex event characterized by an estrogen-rich follicular phase and, after ovulation, a progesterone-rich luteal phase. Each phase lasts about 14 days resulting in an inter-menstrual interval of about 28 days. The endometrial tissue responds to the changes in hormonal levels.
The onset of menstruation is the beginning of a new menstrual cycle and is counted as day one. During a span of about five to seven days, the superficial layers of the endometrium, which grew and developed during the antecedent ovarian/menstrual cycle, are sloughed because demise of the corpus luteum in the non-fertile menstrual cycle is associated with the loss of progesterone secretion. Ovarian follicular maturation occurs progressively resulting in a rise in the circulating levels of estrogen, which in turn leads to new endometrial proliferation.
The dominant ovarian follicle undergoes ovulation at mid-cycle, generally between menstrual cycle days 12 to 16 and is converted from a predominantly estrogen source to a predominantly progesterone source (the corpus luteum). The increasing level of progesterone in the blood converts the proliferative endometrium to a secretory phase in which the tissue proliferation has promptly abated, leading to the formation of endometrial glands or organs. When the ovulated oocyte is viably fertilized and continues its progressive embryonic cleavage, the secretory endometrium and the conceptus can interact to bring about implantation, beginning about six to eight days after fertilization.
If an ongoing pregnancy is to be established by implantation, the embryo will attach and burrow into the secretory endometrium and begin to produce human chorionic gonadotropin (HCG). The HCG in turn stimulates extended corpus luteum function, i.e., the progesterone function remains elevated, and menses does not occur in the fertile menstrual cycle. Pregnancy is then established.
In the non-fertile menstrual cycle, the waning level of progesterone in the blood causes the endometrial tissue to be sloughed. This starts a subsequent menstrual cycle.
Because endometrial proliferation serves to prepare the uterus for an impending pregnancy, manipulation of hormones for the uterine environment can provide contraception. For example, estrogens are known to decrease follicle stimulating hormone secretion by feedback inhibition. Under certain circumstances, estrogens can also inhibit luteinizing hormone secretion, once again by negative feedback. Under normal circumstances the spike of circulating estrogen found prior to ovulation induces the surge of gonadotropic hormones that occurs just prior to and resulting in ovulation. High doses of estrogen can prevent conception probably due to interference with implantation.
Progestins can also provide contraception. Endogenous progesterone is responsible for the progestational changes in the endometrium and the cyclic changes of cells and tissue in the cervix and the vagina. Administration of progestin makes the cervical mucus thick, tenacious and cellular, which is believed to impede spermatozoal transport. Administration of progestin also inhibits luteinizing hormone secretion and blocks ovulation in humans.
There are a number of contraceptive formulations currently on the market that can be classified readily into several general types. The first of these are known as monophasic formulations. Monophasic formulations contain a constant amount of estrogen and progestin. Nuisance side effects with monophasic formulation pills depend on the balance between the estrogen and progestin component of the pill. For example, with a relatively dominant progestin pill, the formulation will, over time, result in a depletion of both estrogen and progestin receptors. The result, which might be expected, is an under stimulated or atrophic endometrium, which may eventually cause either un-pill amenorrhea or breakthrough bleeding or spotting due to poor epithelialization. On the other hand, with a relatively dominant estrogenic preparation, it is possible that prolonged use could result in endometrial growth with the development of unsupported fragile stroma and subsequent spotting or breakthrough bleeding.
New formulations known as triphasics have varying levels of estrogen and progestin; in most cases consisting of relatively constant levels of estrogen with a step-wise increase in progestin throughout the cycle. This pattern of estrogen and progestin administration results in a relatively dominant estrogenic formulation at the beginning of the package with increasing progestigenic activity toward the end of the package. Endometrial stability may be better with these pills since the estrogenic activity at the beginning of the package induces both estrogen and progestin receptors making the endometrium sensitive to the increased levels of progestin towards the end of the package. The progestin activity produces denser, more stable endometrial stroma although the relatively long duration of progestin exposure, toward the end of the package, may still lead to decreased estrogen and progestin receptors and activity.
A significant problem with this type of formulation is the low dose of steroids at the beginning of the package, which makes these pills vulnerable to drug interactions, or missed pills, which may lead to breakthrough ovulation. The beginning of the package is the critical time in terms of breakthrough ovulation since the user has just completed a seven day drug-free interval during which follicular development may begin. Even if pregnancy does not occur, breakthrough ovulation can lead to poor cycle control.
17-β-estradiol (E2) is the most potent natural estrogen found in human beings and is the major secretory product of the ovary. It is readily oxidized in the body to estrone E, which in turn can be hydrated to estriol. These transformations take place mainly in the liver, where there is free interconversion between E1 and estradiol. All three of these natural estrogens are excreted in the urine as glucuronides and sulfates, along with a host of related, minor products in water-soluble complexes. It is widely known that, following oral administration of micronized E2, the incremental circulation of estrogen is principally the less active species E1, which reaches a peak concentration many times greater than that of E2. The conversion of E2 to E1 and subsequently to other metabolites takes place during absorption from the intestine and passage through the liver. This extensive metabolism greatly limits the oral effectiveness of the natural estrogens and their esters. Indeed, because of their limited oral efficacy, E2 and its esters are generally administered by intramuscular injections.
Progesterone (P4) is the active natural progestin, which occurs in the corpus luteum, placenta and adrenal cortex. Like E2, P4 is also ineffective by oral administration because of its rapid metabolism in the intestinal epithelium and in the liver, and is therefore only administered intramuscularly.
Because of their limited oral effectiveness, workers in the art consider these natural female sex hormones as undesirable in the formulation of oral contraceptives. Instead, workers have focused on the fabrication and administration of synthetic estrogens and progestins for contraceptive purposes. The use of synthetic derivatives has also replaced natural substances in the treatment of menopause, threatened abortion, etc. However, these synthetic derivatives are more likely to cause toxic side effects than are the relatively safe endogenous hormones.
While chemical modifications of natural hormones exhibit enhanced oral activity, they also can cause a variety of undesirable side effects. For example, synthetic derivatives of natural hormones are known to have an adverse stimulating effect on the protein synthesis of the liver (possibly promoting thrombosis) and exhibit a diabetogenic effect, in contrast to natural sex hormones.
Synthetic estrogen, for example, is rapidly resorbed in the stomach and intestinal track. Because it is easily metabolized, it is rapidly absorbed in the mucus membrane of the small intestine and/or undergoes rapid chemical changes. Consequently, large individual differences in bio-availability can result. Further, synthetic estradiols can lead to an undesirable accumulation of certain zenobiotics and are known to exhibit carcinogenic properties.
Synthetic progestins are also known to exhibit undesirable side effects including, for example, masculinization and adverse effects on cholesterol levels, triglyceride levels and high-density lipoprotein levels. Synthetic progestins can also cause fluid retention and depression.
An additional undesirable side effect that can affect subjects undergoing synthetic hormonal contraceptive treatment is the reduction/cessation of natural hormone production. Many subjects also experience an undesirable hormone imbalance resulting from the cessation of ovulation due to the contraceptive effect of administered synthetic hormones.
Accordingly, there is an urgent need for a pharmaceutical formulation that includes endogenous hormones that can be administered in amounts effective to provide not only a contraceptive effect but also a hormone-replacement effect.